Effects of 17beta;-Estradiol on Colonic Permeability and Inflammation in an Azoxymethane/Dextran Sulfate Sodium-Induced Colitis Mouse Model

Nov 8, 2018Gut and liver

Effects of 17β-Estradiol on Gut Leakiness and Inflammation in a Mouse Model of Colon Inflammation

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Abstract

E2 treatment reduced -mediated damage score and activity (p＜0.05).

Colonic permeability and inflammation may be reduced in a mouse model of colon cancer through estradiol treatment.
AOM/DSS treatment decreased the expression of intestinal barrier-related molecules, including MUC2, ZO-1, OCLN, and CLDN4.
Estradiol supplementation appeared to restore the expression of these intestinal barrier-related molecules.
Inflammation-related gene expression, including KLF4, NF-κB, iNOS, and COX-2, was increased by AOM/DSS treatment but decreased with E2 treatment.
E2 may exert its effects via the estrogen receptor β signaling pathway.

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BACKGROUND/AIMS: Intestinal barrier dysfunction is a hallmark of inflammatory bowel diseases (IBDs) such as ulcerative . This dysfunction is caused by increased permeability and the loss of in intestinal epithelial cells. The aim of this study was to investigate whether estradiol treatment reduces colonic permeability, tight junction disruption, and inflammation in an azoxymethane (AOM)/dextran sodium sulfate (DSS) colon cancer mouse model.

METHODS: The effects of 17β-estradiol (E2) were evaluated in ICR male mice 4 weeks after AOM/DSS treatment. Histological damage was scored by hematoxylin and eosin staining and the levels of the colonic mucosal cytokine (MPO) were assessed by enzyme-linked immunosorbent assay (ELISA). To evaluate the effects of E2 on intestinal permeability, tight junctions, and inflammation, we performed quantitative real-time polymerase chain reaction and Western blot analysis. Furthermore, the expression levels of mucin 2 (MUC2) and mucin 4 (MUC4) were measured as target genes for intestinal permeability, whereas zonula occludens 1 (ZO-1), occludin (OCLN), and claudin 4 (CLDN4) served as target genes for the tight junctions.

RESULTS: The colitis-mediated induced damage score and MPO activity were reduced by E2 treatment (p＜0.05). In addition, the mRNA expression levels of intestinal barrier-related molecules (i.e., MUC2, ZO-1, OCLN, and CLDN4) were decreased by AOM/DSS-treatment; furthermore, this inhibition was rescued by E2 supplementation. The mRNA and protein expression of inflammation-related genes (i.e., KLF4, NF-κB, iNOS, and COX-2) was increased by AOM/DSS-treatment and ameliorated by E2.

CONCLUSIONS: E2 acts through the estrogen receptor β signaling pathway to elicit anti-inflammatory effects on intestinal barrier by inducing the expression of MUC2 and tight junction molecules and inhibiting pro-inflammatory cytokines.

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p=0.015

Decrease in Activity

Statistical significance of activity reduction in E2-treated male mice.

p<0.001

MUC2 Expression Recovery

MUC2 mRNA expression recovery in AOM/DSS-treated male mice with E2.

p=0.001

ZO-1 Expression Recovery

ZO-1 mRNA expression recovery in AOM/DSS-treated male mice with E2.

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Effects of 17beta;-Estradiol on Colonic Permeability and Inflammation in an Azoxymethane/Dextran Sulfate Sodium-Induced Colitis Mouse Model

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